Natural killer (NK) cells, the third major population of lymphocytes, have the capacity to kill tumor and virus-infected cells and to produce immuno-modulatory cytokines without the need for prior immunization. Emerging evidence indicates that variation in genes encoding killer immunoglobulin-like receptor (KIR), expressed by natural killer (NK) cells, and HLA ligands can significantly influence disease susceptibility and progression. Recent genetic association studies have revealed that individuals with specific KIR and HLA genotypes are at greater risk of developing cancer. The fact that different ethnic populations display varying trends in their KIR-HLA genotypes offers a strong potential explanation for documented cancer health disparities. Although these epidemiological studies highlight the importance of the interplay between KIR and HLA in disease, the functional basis for this association has been poorly understood. Recently, we have found an important novel role for these MHC recognizing receptors on NK cells, in both mice and humans. Our findings indicate that the interaction between these receptors and the MHC I ligand is required to confer functional competence in a process we have termed licensing. Licensing has provided a satisfactory explanation for how an NK cell acquires potency, yet achieves tolerance to self-tissues. The licensing impact has been fully analyzed in a murine NK cell system where we found that licensing has a positive effect on all aspects of NK cell responsiveness to various stimuli. This global influence, however, was not observed in human NK cells. Our previous studies have shown that licensing through KIR3DL1 impacted the responsiveness of NK cells to tumor cells, but it did not influence the responsiveness to stimulation through Fc-gamma receptor (CD16), which mediates lysis of antibody-coated target cells. However, studies by other groups, with a small number of samples, have reported that licensing through other KIR impacted the NK cell response both to tumor cells and to stimulation through CD16. Together, these studies formulate a hypothesis that different KIRs have distinct impacts on the responsiveness of NK cells via stimulation through CD16 and/or to other activation receptors. In this proposal we will determine the impact of licensing through two different KIR, KIR3DL1 and 2DL3, on the responsiveness of NK cells to stimulation through CD16 and other activation receptors known to be involved in tumor recognition. Since licensing appears to be critical for the functional competence of NK cells, our study will generate critical data for furthering our understanding of the impact of licensing on the resolution of disease, especially in the context of health disparities among different ethnic populations, and provide the functional explanation for the results of the KIR-HLA disease association studies. PUBLIC HEALTH RELEVANCE: This project is directed at understanding the population based differences in innate immunity that result in cancer health disparities. Specifically, the project seeks to define the anti-tumor activity of natural killer cells by studying the genes that control both the killer cell receptor molecules and the target tumor markers. This understanding will lead to novel strategies to enhance innate anti-cancer immunity and address disparities in cancer incidence.